Abstract 496: Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination

Protein deubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. Ubiquitin specific peptidases (USPs) remove ubiqiuitin tags from target proteins to control both protein fate and function. USP37 (Ubiquitin specific peptidase 37) has been implicated in cancer and we have previously shown that antagonizes the tumor suppressor APC CDH1 and promotes S phase entry. However, the role of USP37 during S-phase was unknown. Here, we report that in cells experiencing replication stress USP37 overexpression confers survival advantage while its depletion enhances sensitivity. USP37 overexpressing cells were able to resolve different DNA damage markers much more effectively then the control cells or cells in which USP37 was depleted. Mechanistically, our data indicate that USP37 binds and stabilizes the active form of CHK1 and deubiquitinates Chk1 to increase its stability and promote the checkpoint response. USP37 overexpression results in constitutive replication fork movement and long tract DNA synthesis while USP37 depleted cells were unable to carry out long tract DNA synthesis. Notably, expression of low level of Chk1 in USP37 depleted cells rescues cell survival and DNA damage response. Overall our data suggest that inhibition of USP37 may represent a novel mechanism to modulate Chk1 activity. Note: This abstract was not presented at the meeting. Citation Format: Mayank Singh, Amy C. Burrows, Andrew Dickson, Komal Komal, Debjani Pal, Matthew K. Summers. Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2017-496